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Nature Communications Jul 2023Ensitrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro or Nsp5), is clinically useful against SARS-CoV-2 including its omicron variants....
Ensitrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro or Nsp5), is clinically useful against SARS-CoV-2 including its omicron variants. Since most omicron subvariants have reduced sensitivity to most monoclonal antibody therapies, SARS-CoV-2 resistance to other antivirals including main protease inhibitors such as ensitrelvir is a major public health concern. Here, repeating passages of SARS-CoV-2 in the presence of ensitrelvir revealed that the M49L and E166A substitutions in Nsp5 are responsible for reduced sensitivity to ensitrelvir. Both substitutions reduced in vitro virus growth in the absence of ensitrelvir. The combination of the M49L and E166A substitutions allowed the virus to largely evade the suppressive effect of ensitrelvir in vitro. The virus possessing Nsp5-M49L showed similar pathogenicity to wild-type virus, whereas the virus possessing Nsp5-E166A or Nsp5-M49L/E166A slightly attenuated. Ensitrelvir treatment of hamsters infected with the virus possessing Nsp5-M49L/E166A was ineffective; however, nirmatrelvir or molnupiravir treatment was effective. Therefore, it is important to closely monitor the emergence of ensitrelvir-resistant SARS-CoV-2 variants to guide antiviral treatment selection.
Topics: Animals; Cricetinae; COVID-19; SARS-CoV-2; Antiviral Agents
PubMed: 37454219
DOI: 10.1038/s41467-023-40018-1 -
Angewandte Chemie (International Ed. in... Jul 2021Werner's Complex, as a cationic coordination complex (CCC), has hitherto unappreciated biological properties derived from its binding affinity to highly anionic...
Werner's Complex, as a cationic coordination complex (CCC), has hitherto unappreciated biological properties derived from its binding affinity to highly anionic biomolecules such as glycosaminoglycans (GAGs) and nucleic acids. Competitive inhibitor and spectroscopic assays confirm the high affinity to GAGs heparin, heparan sulfate (HS), and its pentasaccharide mimetic Fondaparinux (FPX). Functional consequences of this affinity include inhibition of FPX cleavage by bacterial heparinase and mammalian heparanase enzymes with inhibition of cellular invasion and migration. Werner's Complex is a very efficient condensing agent for DNA and tRNA. In proof-of-principle for translational implications, it is demonstrated to display antiviral activity against human cytomegalovirus (HCMV) at micromolar concentrations with promising selectivity. Exploitation of non-covalent hydrogen-bonding and electrostatic interactions has motivated the unprecedented discovery of these properties, opening new avenues of research for this iconic compound.
Topics: Antiviral Agents; Coordination Complexes; Cytomegalovirus; Fondaparinux; Glycosaminoglycans; Humans; Microbial Sensitivity Tests
PubMed: 34105220
DOI: 10.1002/anie.202105019 -
Current Opinion in Pediatrics Jun 2023To review the epidemiology, clinical manifestations, and treatment strategies of nonpolio enterovirus and parechovirus (PeV) infections, and identify research gaps. (Review)
Review
PURPOSE OF REVIEW
To review the epidemiology, clinical manifestations, and treatment strategies of nonpolio enterovirus and parechovirus (PeV) infections, and identify research gaps.
RECENT FINDINGS
There is currently no approved antiviral agent for enterovirus or PeV infections, although pocapavir may be provided on a compassionate basis. Elucidation of the structure and functional features of enterovirus and PeV may lead to novel therapeutic strategies, including vaccine development.
SUMMARY
Nonpolio human enterovirus and PeV are common childhood infections that are most severe among neonates and young infants. Although most infections are asymptomatic, severe disease resulting in substantial morbidity and mortality occurs worldwide and has been associated with local outbreaks. Long-term sequelae are not well understood but have been reported following neonatal infection of the central nervous system. The lack of antiviral treatment and effective vaccines highlight important knowledge gaps. Active surveillance ultimately may inform preventive strategies.
Topics: Infant, Newborn; Infant; Humans; Child; Enterovirus; Parechovirus; Enterovirus Infections; Antiviral Agents; Disease Outbreaks; Picornaviridae Infections
PubMed: 36876331
DOI: 10.1097/MOP.0000000000001236 -
Molecules (Basel, Switzerland) Nov 2021The treatment of viral disease has become a medical challenge because of the increasing incidence and prevalence of human viral pathogens, as well as the lack of viable... (Review)
Review
The treatment of viral disease has become a medical challenge because of the increasing incidence and prevalence of human viral pathogens, as well as the lack of viable treatment alternatives, including plant-derived strategies. This review attempts to investigate the trends of research on in vitro antiviral effects of curcumin against different classes of human viral pathogens worldwide. Various electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar were searched for published English articles evaluating the anti-viral activity of curcumin. Data were then extracted and analyzed. The forty-three studies (published from 1993 to 2020) that were identified contain data for 24 different viruses. The 50% cytotoxic concentration (CC50), 50% effective/inhibitory concentration (EC50/IC50), and stimulation index (SI) parameters showed that curcumin had antiviral activity against viruses causing diseases in humans. Data presented in this review highlight the potential antiviral applications of curcumin and open new avenues for further experiments on the clinical applications of curcumin and its derivatives.
Topics: Antiviral Agents; Curcumin; Humans; Virus Diseases
PubMed: 34834089
DOI: 10.3390/molecules26226994 -
Wiley Interdisciplinary Reviews.... Sep 2022The COVID-19 pandemic has inspired large research investments from the global scientific community in the study of viral properties and antiviral technologies (e.g.,... (Review)
Review
The COVID-19 pandemic has inspired large research investments from the global scientific community in the study of viral properties and antiviral technologies (e.g., self-cleaning surfaces, virucides, antiviral drugs, and vaccines). Emerging viruses are a constant threat due to the substantial variation in viral structures, limiting the potential for expanded broad-spectrum antiviral agent development, and the complexity of targeting multiple and diverse viral species with unique characteristics involving their virulence. Multiple, more infectious variants of SARS-CoV2 (e.g., Delta, Omicron) have already appeared, necessitating research into versatile, robust control strategies in response to the looming threat of future viruses. Nanotechnology and nanomaterials have played a vital role in addressing current viral threats, from mRNA-based vaccines to nanoparticle-based drugs and nanotechnology enhanced disinfection methods. Rapid progress in the field has prompted a review of the current literature primarily focused on nanotechnology-based virucides and antivirals. In this review, a brief description of antiviral drugs is provided first as background with most of the discussion focused on key design considerations for high-efficacy antiviral nanomaterials (e.g., nanopharmaceuticals) as determined from published studies as well as related modes of biological activity. Insights into potential future research directions are also provided with a section devoted specifically to the SARS-CoV2 virus. This article is categorized under: Toxicology and Regulatory Issues in Nanomediciney > Toxicology of Nanomaterials Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease.
Topics: Antiviral Agents; Humans; Pandemics; RNA, Viral; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35697665
DOI: 10.1002/wnan.1823 -
Viruses Aug 2022Enterovirus infections affect people around the world, causing a range of illnesses, from mild fevers to severe, potentially fatal conditions. There are no approved...
Enterovirus infections affect people around the world, causing a range of illnesses, from mild fevers to severe, potentially fatal conditions. There are no approved treatments for enterovirus infections. We have tested our library of broad-spectrum antiviral agents (BSAs) against echovirus 1 (EV1) in human adenocarcinoma alveolar basal epithelial A549 cells. We also tested combinations of the most active compounds against EV1 in A549 and human immortalized retinal pigment epithelium RPE cells. We confirmed anti-enteroviral activities of pleconaril, rupintrivir, cycloheximide, vemurafenib, remdesivir, emetine, and anisomycin and identified novel synergistic rupintrivir-vemurafenib, vemurafenib-pleconaril and rupintrivir-pleconaril combinations against EV1 infection. Because rupintrivir, vemurafenib, and pleconaril require lower concentrations to inhibit enterovirus replication in vitro when combined, their cocktails may have fewer side effects in vivo and, therefore, should be further explored in preclinical and clinical trials against EV1 and other enterovirus infections.
Topics: Anisomycin; Antiviral Agents; Cycloheximide; Drug Combinations; Emetine; Enterovirus Infections; Humans; Picornaviridae; Vemurafenib
PubMed: 36146673
DOI: 10.3390/v14091866 -
Advances in Experimental Medicine and... 2022Hepatitis C virus (HCV) infection affects approximately 1% of the world's population and is a major cause of chronic liver diseases. Although antiviral therapy...
Hepatitis C virus (HCV) infection affects approximately 1% of the world's population and is a major cause of chronic liver diseases. Although antiviral therapy consisting of direct-acting antivirals (DAAs) can cure the majority of HCV patients, it is still limited by viral resistances, drug-drug interactions, and high costs. Moreover, the role of DAAs in the prevention of occurrences of graft reinfection in HCV patients who receive liver transplantations is still under comprehensive clinical investigation, bringing the risk of recipient reinfection. HCV entry is composed of initial non-specific attachment and binding, post-binding interactions with essential host factors, internalization, and virion-cell membrane fusion to release viral RNA to cytosol. Thus, a number of novel and promising targets from either virion or cellular factors of these processes become optimal interfering elements for antiviral therapy, eliminating viral infection at the very beginning. Therefore, entry inhibitors can be supplemented into the future treatment regimens to optimize and widen the prevention and therapeutics of HCV infection. This chapter introduces the basic HCV entry processes and summarizes molecular mechanisms and research status of the current antiviral agents targeting HCV entry in preclinical and clinical study.
Topics: Antiviral Agents; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Reinfection; Virus Internalization
PubMed: 35412143
DOI: 10.1007/978-981-16-8702-0_13 -
Pharmacology & Therapeutics May 2022Responding quickly to emerging respiratory viruses, such as SARS-CoV-2 the causative agent of coronavirus disease 2019 (COVID-19) pandemic, is essential to stop... (Review)
Review
Responding quickly to emerging respiratory viruses, such as SARS-CoV-2 the causative agent of coronavirus disease 2019 (COVID-19) pandemic, is essential to stop uncontrolled spread of these pathogens and mitigate their socio-economic impact globally. This can be achieved through drug repurposing, which tackles inherent time- and resource-consuming processes associated with conventional drug discovery and development. In this review, we examine key preclinical and clinical therapeutic and prophylactic approaches that have been applied for treatment of SARS-CoV-2 infection. We break these strategies down into virus- versus host-targeting and discuss their reported efficacy, advantages, and disadvantages. Importantly, we highlight emerging evidence on application of host serine protease-inhibiting anticoagulants, such as nafamostat mesylate, as a potentially powerful therapy to inhibit virus activation and offer cross-protection against multiple strains of coronavirus, lower inflammatory response independent of its antiviral effect, and modulate clotting problems seen in COVID-19 pneumonia.
Topics: Anticoagulants; Antiviral Agents; Humans; Pandemics; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34718070
DOI: 10.1016/j.pharmthera.2021.108027 -
Reviews in Medical Virology Jul 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus and the causative agent of coronavirus disease 2019 (Covid-19). There is an... (Review)
Review
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus and the causative agent of coronavirus disease 2019 (Covid-19). There is an urgent need for effective antivirals to treat current Covid-19 cases and protect those unable to be vaccinated against SARS-CoV-2. Marine molluscs live in an environment containing high virus densities (>10 virus particles per ml), and there are an estimated 100,000 species in the phylum Mollusca, demonstrating the success of their innate immune system. Mollusc-derived antivirals are yet to be used clinically despite the activity of many extracts, including against human viruses, being demonstrated in vitro. Hemolymph of the Pacific oyster (Crassostrea gigas) has in vitro antiviral activity against herpes simplex virus and human adenovirus, while antiviral action against SARS-CoV-2 has been proposed by in silico studies. Such evidence suggests that molluscs, and in particular C. gigas hemolymph, may represent a source of antivirals for human coronaviruses.
Topics: Animals; Antiviral Agents; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34726308
DOI: 10.1002/rmv.2310 -
Molecules (Basel, Switzerland) Oct 2022In recent decades, heparin, as the most important anticoagulant drug, has been widely used in clinical settings to prevent and treat thrombosis in a variety of diseases.... (Review)
Review
In recent decades, heparin, as the most important anticoagulant drug, has been widely used in clinical settings to prevent and treat thrombosis in a variety of diseases. However, with in-depth research, the therapeutic potential of heparin is being explored beyond anticoagulation. To date, heparin and its derivatives have been tested in the protection against and repair of inflammatory, antitumor, and cardiovascular diseases. It has also been explored as an antiangiogenic, preventive, and antiviral agent for atherosclerosis. This review focused on the new and old applications of heparin and discussed the potential mechanisms explaining the biological diversity of heparin.
Topics: Humans; Heparin; Anticoagulants; Thrombosis; Cardiovascular Diseases; Antiviral Agents
PubMed: 36296562
DOI: 10.3390/molecules27206968